INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Ji Wang,Yanhao Zhang,Shuo Dong,Wenhui Zha,Chao Liu,Yang Wang,Yuhao Jiang,Hanlei Xing,Xinsong Li
Lipid nanoparticles (LNPs)-based mRNA vaccines have shown great potential in the fight against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, it remains still a challenge to improve the delivery efficiency of LNPs and the long-term stability of their mediated mRNA vaccines. Herein, a novel ionizable lipid 2-hexyldecyl 6-(ethyl(3-((2-hexyldecyl)oxy)-2-hydroxypropyl)amino)hexanoate (HEAH) derived LNPs were developed for delivering the receptor binding domain (RBD) mRNAs. In vitro cell assays confirmed that the ionizable lipid HEAH with one ether bond and one ester bond derived LNPs possessed higher mRNA delivery efficiency compared with the approved ALC-0315 with two ester bonds used in the BNT162b2 vaccine. Notably, the HEAH-derived LNPs powder lyophilized did not significantly change for 30 days after storage at 37 °C indicating good thermostability. After two RBD mRNAs of Delta and Omicron variants were encapsulated into the HEAH-derived LNPs, a bivalent mRNA vaccine was obtained as a nanoparticle formulation. Importantly, the bivalent mRNA vaccine not only resisted Delta and Omicron and also generated protective antibodies against ancestral SARS-CoV-2. The HEAH-mediated bivalent vaccine induced stronger humoral and cellular immunity than those of the ALC-0315 group. Taken together, the ionizable lipid HEAH-derived LNPs show outstanding potential in improving the delivery efficiency of mRNA and the stability of mRNA vaccine.
研究领域:
药学
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分子生物学
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病毒学
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纳米技术
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高影响因子
MACROMOLECULAR BIOSCIENCE
·
2026
·Vol. 26
·期 7
·e70220
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IF 4.2
Luwei Zhang,Yuduo Gao,Zhenghao Hu,Yiqing Chen,Chengfan Wu,Qi Shuai,Yunfeng Yan
Nanoparticle (NP) carriers are critical for enhancing the stability and cellular uptake of mRNA, enabling its therapeutic potential. However, conventional mRNA NP carriers enter cells via endocytosis, followed by endosome-lysosome trafficking, which leads to inefficient mRNA release into the cytoplasm. This insufficient endosomal escape has become a challenge in improving mRNA delivery efficiency for polymer and lipid NP carriers. In this study, we design a novel class of lipoic acid derivative (LA-Der) composite NPs with surface disulfide bonds that anchor onto cell membranes through disulfide exchange with cell surface thiols, bypassing endosomal degradation and directly releasing mRNA into the cytoplasm. We synthesized 25 LA-Ders with diverse chemical structures via amidation and incorporated 10 kDa polyethyleneimine (PEI) to form composite NPs for optimal mRNA loading. In vitro optimization identified three LA-Der/PEI formulations, LA-4A1, LA-5A1, and LA-6A2, as the most effective for mRNA delivery. Mechanistic studies revealed that thiol-mediated uptake is the predominant internalization pathway, facilitating the bypass of endosomal barriers. In vivo experiments confirmed high luciferase expression in the spleen and liver following intravenous injection of NPs carrying luciferase mRNA. These LA-Der/PEI composite NPs provide a promising strategy for overcoming intracellular endosomal escape barriers, advancing the clinical translation of mRNA therapeutics.
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Animals
·
2026
·Vol. 16
·期 14
·2274
·
IF 3.2
Yusheng Lin,Jinxiu Jiang,Weiwei Liu,Kul Raj Rai,Yongliang Che
Simple SummaryA new mRNA vaccine candidate encoding the ORFV F1L protein (F1L-mRNA-LNP) was developed and evaluated in mice against a commercial live vaccine. At a 10 μg dose, the mRNA vaccine elicited cellular immune responses comparable to the commercial vaccine and conferred equivalent protective efficacy upon viral challenge. Although humoral antibody responses were relatively lower, the vaccine demonstrated clear protective potential. These findings position F1L-mRNA-LNP as a promising candidate for ORFV control, warranting further preclinical and translational studies.Orf virus (ORFV) is a major pathogen in goats and sheep, and control currently depends mainly on commercial live vaccines. Although mRNA vaccines have revolutionized human medicine, their use in veterinary settings is largely unexplored. In this study, an mRNA vaccine candidate encoding the ORFV F1L protein (F1L-mRNA-LNP) was developed via in vitro transcription and encapsulated in lipid nanoparticles. BALB/c mice were divided into five groups (n = 14 each): three receiving different doses of F1L-mRNA-LNP (5, 10, or 15 μg), one receiving a commercial live vaccine (CV), and a PBS control group. Mice were immunized intramuscularly and boosted after 14 days; immune responses were assessed 14 days later following ARRIVE 2.0 guidelines. Both the F1L-mRNA-LNP and CV vaccines induced specific antibodies versus PBS (p< 0.01). The 10 μg mRNA group showed Th1 cytokine and CD8+T cell responses comparable to CV (p> 0.05), whereas IL-4 (Th2) was significantly higher in the CV group (p< 0.05). Neutralizing antibody titers did not differ between groups, indicating that the mRNA vaccine induces comparable Th1 cellular immunity but weaker Th2 humoral immunity. Upon ORFV challenge, the 10 μg F1L-mRNA-LNP vaccine protected BALB/c mice, as evidenced by stable body weight, no clinical symptoms, and reduced viral load, with efficacy comparable to CV (p> 0.05). This study provides strong evidence supporting the optimization of ORFV mRNA vaccines and highlights the translational potential of the F1L-mRNA-LNP candidate vaccine for veterinary applications.
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Journal of the American Chemical Society
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2026
·
IF 16.6
Chenlong Wei,Xinzhu Shan,Yuxuan Huang,Bin Ma,Zhiqiang Zhao,Yian Fang,Chengrui Bai,Zihan Zhang,Peng Zhao,Huijuan Zhang,Yu Hou,Tianjiao Ji,Zhongtang Li,Song Song,Fei Xie,Lei Miao
The inefficient delivery of lipid nanoparticles (LNPs)-encapsulated mRNA to activated fibroblasts in fibrotic tissues remains a major challenge for antifibrotic therapy. To overcome this, we develop a fibrosis organ and cell unified-targeting system (FOCUS) for mRNA delivery with LNPs. FOCUS LNPs combines an ionizable lipid library (synthesized via Ugi multicomponent reactions) with fibroblast activation protein-α (FAP)-targeting lipid-like ligands. These LNPs achieve ∼3-fold and ∼12-fold greater mRNA expression in fibrotic liver and lung, along with ∼2–5-fold higher fibroblast distribution─unattainable by organ- or ligand-only targeting. As proof of concept, Pentraxin-2 mRNA (mPTX-2)-loaded FOCUS LNPs drive localized PTX-2 production in murine models of pulmonary and hepatic fibrosis, reducing collagen deposition by 60–80% while avoiding systemic side effects like impaired wound healing. Mechanistically, mPTX-2 FOCUS LNPs suppress monocyte-to-fibrocyte differentiation, M2 macrophage polarization, and fibroblast activation. This work establishes a precision mRNA delivery platform for fibrotic diseases, offering a safer and more effective therapeutic strategy.
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CARDIOVASCULAR RESEARCH
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2025
·
IF 13.3
Zhang Huawei,Liu Jing,Sun Daqian,Liu Yuxiu,Sun Wenhao,Wang Shanshan,Xu Xiuqin
AimsVascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets.Methods and ResultsWe established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor (PDGF)-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or Nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling.ConclusionsThis study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.
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Genes & Diseases
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2026
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IF 14.6
Xinhang Li,Yi Xie,Wenyan Ren,Qing Liu,Qiming Pang,Wenting Liu,Xin Li,Bin He,Dongmei He,Xinyue Wan,Jia Liu,Jie Cai,Baicheng He,Wei Huang,Fang He
Renal osteodystrophy is a debilitating complication of chronic kidney disease characterized by deteriorated bone microarchitecture and impaired bone formation, leading to increased fracture risk. Despite the pressing need for anabolic therapies, the cellular mechanisms by which uremic stress compromises osteoprogenitor function remain poorly defined. Here, metabolomic profiling of renal osteodystrophy patient cohorts revealed a profound depletion of circulating betaine. We show that betaine supplementation not only rescued the osteogenic differentiation of bone marrow-derived mesenchymal stem cells challenged with the uremic toxin indoxyl sulfate but also ameliorated skeletal deterioration in a rat model of chronic kidney disease. Mechanistically, we demonstrated that indoxyl sulfate triggered ferroptosis in bone marrow-derived mesenchymal stem cells—characterized by iron-dependent lipid peroxidation and aberrant HMOX1 up-regulation—thereby arresting osteogenesis. Betaine mitigates this ferroptotic stress through a novel post-transcriptional mechanism. Specifically, betaine down-regulated the RNA-binding protein hnRNP A1, preventing the recruitment of the CNOT1 deadenylase complex. This inhibition stabilized Abcg1 mRNA, leading to restored ABCG1 expression. Functional perturbation studies confirmed that the ABCG1–HMOX1 axis was indispensable for the anti-ferroptotic and osteoprotective effects of betaine. Collectively, our findings delineate a Betaine–hnRNP A1/CNOT1–ABCG1–HMOX1 signaling cascade that links metabolic deficiency to ferroptosis-driven osteogenic failure, positioning betaine as a promising anabolic therapeutic strategy for renal osteodystrophy.
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Materials Today
·
2026
·
IF 24.1
Ziyue An,Yibo Qi,Pingjie Sun,Kuncheng Lv,Sheng Ma,Wantong Song,Xuesi Chen
Cytosolic delivery is the fundamental prerequisite for messenger RNA (mRNA) therapeutics. However, most delivery systems rely on endocytosis and are limited by inefficient endosomal escape, suffering from low delivery efficiency and strong dose dependence. Here, we report a ctivatable m embrane- d estabilizing lipid- p olycations (AMDPs) that enable a predominantly non-endocytic mRNA delivery via cell-membrane anchoring and destabilization. AMDPs are constructed by introducing esterase-labile quaternary ammonium side chains with hydrophobic motifs onto a poly(L-lysine) backbone, allowing stable mRNA complexation through electrostatic and hydrophobic interactions. Upon enzymatic activation, AMDPs undergo a cascade-triggered cleavage process, in which the hydrophobic moieties are removed to expose carboxylates adjacent to cationic alkyl chains. This transformation generates an inverse phospholipid-like zwitterionic architecture that promotes membrane pairing and localized destabilization, enabling direct cytosolic release of mRNA. AMDPs realizes dose-independent transfection, with 6.25 ng mRNA producing protein expression comparable to 200 ng, corresponding to a 32-fold reduction in mRNA input. Following intravenous administration, AMDPs achieve liver-selective mRNA expression, with 95% of total protein expression confined to the liver. Therapeutic delivery of interleukin-10 and relaxin mRNAs significantly attenuates fibrosis and restores liver architecture in a CCl 4 -induced mouse model. This work establishes a mechanistically distinct and non-endocytic strategy for low-dose and organ-targeted mRNA therapy. Download: Download high-res image (164KB) Download: Download full-size image
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Nature Communications
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2026
·
IF 18.1
Zhijian Zhu,Rui Zhang,Haoran Kang,Meiyuan Chen,Hengjun Huang,Jing Wang,Ling Guo,Yuxing Li,Wenjing Chen,Limin Meng,Ruisi Wang,Ling Li,Kong-Peng Lam,Shengli Xu,Xijun Ou
Heterogeneous nuclear ribonucleoproteins (hnRNP) are key regulators of gene expression, yet the physiological functions of the highly homologous hnRNP A1 and A2B1 in B cells remain unclear. Here, we conditionally delete Hnrnpa1 and Hnrnpa2b1 in mouse B cells and find that loss of hnRNP A1 and A2B1 compromises the germinal center (GC) reaction during T cell-dependent immune responses. Loss of hnRNP A1 and A2B1 impairs GC B cell proliferation and high-affinity antibody production. Mechanistically, hnRNP A1/A2B1 bind UAG-rich motifs in Ezh2 pre-mRNA to promote Ezh2 exon 14 inclusion, thereby preserving EZH2 catalytic activity; in their absence, Ezh2 exon 14-skipping produces a catalytically inactive EZH2 isoform ( Ezh2 Δ14) with diminished repression of the cell cycle inhibitor Cdkn1a . The resulting CDKN1A accumulation restricts B cell proliferation, while Cdkn1a deletion partially rescues the GC defects in B cells deficient for hnRNP A1 and A2B1. Our findings thus uncover an hnRNP A1/A2B1–EZH2–CDKN1A axis that integrates RNA splicing with epigenetic regulation of B cell immunity. hnRNPs are RNA-binding proteins previously reported to regulate B cell differentiation and proliferation. Here, the authors show that hnRNP A1 and A2B1 support the germinal center reaction by retaining catalytically active EZH2, which reduces the cell cycle inhibitor CDKN1A, thereby promoting B cell proliferation.
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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2024
·Vol. 35
·期 1
·1-10
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IF 4.2
Yuan Xinyuan,Wu Tingting,Lu Teliang,Ye Jiandong
Both silicon (Si) and zinc (Zn) ions are essential elements to bone health and their mechanisms for promoting osteogenesis have aroused the extensive attention of researchers. Thereinto, the mechanism by which dual ions promote osteogenic differentiation remains to be elucidated. Herein, the effects of Si and Zn ions on the cytological behaviors of mBMSCs were firstly studied. Then, the molecular mechanism of Si-Zn dual ions regulating the osteogenic differentiation of mBMSCs was investigated via transcriptome sequencing technology. In the single-ion system, Si ion at the concentration of 1.5 mM (Si-1.5) had better comprehensive effects of cell proliferation, ALP activity and osteogenesis-related gene expression levels (ALP, Runx2, OCN, Col-I and BSP); Zn ion at the concentration of 50 μM (Zn-50) demonstrated better combining effects of cell proliferation, ALP activity and same osteogenic genes expression levels. In the dual-ion system, the Si (1.5 mM)-Zn (50 μM) group (Si1.5-Zn50) synthetically enhanced ALP activity and osteogenesis genes compared with single-ion groups. Analysis of the transcriptome sequencing results showed that Si ion had a certain effect on promoting the osteogenic differentiation of mBMSCs; Zn ion had a stronger effect of contributing to a better osteogenic differentiation of mBMSCs than that of Si ion; the Si-Zn dual ions had a synergistic enhancement on conducting to the osteogenic differentiation of mBMSCs compared to single ion (Si or Zn). This study offers a blueprint for exploring the regulation mechanism of osteogenic differentiation by dual ions. Graphical Abstract
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Turkish Journal of Gastroenterology
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2025
·Vol. 36
·期 7
·431
·
IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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药理学
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转化医学
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Biomaterials Science
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2025
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IF 5.7
Yashuai Wang,Xiaoyin Liu,Haiyin Yang,Shuxiang Wang,Shutao Guo,Yuhua Weng,Jinchao Zhang,Luwei Li,Kun Ge,Xing-Jie Liang
Lipid nanoparticles (LNPs) have become an important platform for nucleic acid delivery. However, LNP-mediated delivery to non-hepatic organs and specific cell types remains a non-negligible challenge. As a key component of LNPs, ionizable lipids were rationally designed to adjust the LNPs properties to achieve organ-targeted delivery. The use of the Ugi four-component reaction (Ugi-4CR) as a one-pot multicomponent synthesis strategy to construct ionizable lipid molecules offers advantages, as it enables multidimensional structural diversity of ionizable lipids. We use isocyanides with cyclic tertiary amine substituents to construct ionizable lipids via an Ugi one-pot reaction. Twenty-five ionizable lipid molecules (W1–W25) containing different cyclic tertiary amine hydrophilic heads, linkers, and hydrophobic tails were synthesized. The W19 LNPs exhibited highly selective mRNA delivery to the spleen upon intravenous administration.
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Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Xiaoxuan Hong,Xianfu Li,Xiaolu Han,Jinghu Lou,Yue Li,Jintao Lin,Yi Cheng,Haonan Xing,Hui Zhang,Xiwei Wang,Shuang Zhang,Nan Liu,Zengming Wang,Chunying Cui,Aiping Zheng
During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro . We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.
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